A good deal of evidence suggests an interaction between the opioid and immune systems. The studies proposed here examine the effects of several opioids on a large battery of immune measures with particular emphasis on the effects of chronic administration, the type of opioid administered, the particular immune measure examined and the mechanism whereby the opioids alter immune function. The first specific aim provides background information for these investigations by examining the effects of acute administration of opioids with predominant activity at mu opioid receptors, i.e., methadone, 1-alpha-acetylmethadol (LAAM) and buprenorphine and comparing them to effects already obtained for morphine. Additional data regarding their mu-opioid mechanism of action will he obtained by examining methadone, LAAM and buprenorphine in combination with the mu-selective opioid antagonist naltrexone. Immune function will be assessed with several different rodent in vitro assays, including mitogen and superantigen-induced stimulation of splenic, lymph node and whole-blood lymphocytes, a natural-killer cell assay, assessment of interleukin-2, interferon and nitric oxide production. The second specific aim explores the effects of opioid administration on immune function in rats that are maintained on a regimen in which their drinking water is adulterated with morphine, methadone, LAAM or buprenorphine. In these studies, the effects of chronic opioid administration will he assessed with the measures of immune function outlined in Specific Aim l and with emphasis on the contribution of factors such as type of opioid administered, dose and duration of administration. The analgesic effects of these drugs also will be assessed prior to, during and subsequent to termination of the regimen of chronic opioid administration. The third specific aim investigates the mechanisms which underlie opioid-induced alterations in immune function. In these experiments, we will extend our investigations of the role of the CNS in morphine's immunomodulatory effects by focusing on four specific brain regions, the periaqueductal gray (PAG), nucleus accumbens (NA), ventral tegmental nucleus (VTA) and the basolateral amygdala (BLA). The first series of studies will examine the effects of morphine on immune status when injected directly into those sites. A second series of experiments will determine whether naltrexone can block the effects of systemic morphine when it is injected into the same four sites.